Rare Disease Database

Susac Syndrome

NORD gratefully acknowledges John O. Susac, MD, deceased; Robert Rennebohm, MD; and Robert A. Egan, MD, Director of Neuro-Ophthalmology, Oregon Neurology, for the preparation of this report.

General Discussion

Summary

Susac syndrome is a relatively rare disorder characterized by three main problems: impaired brain function (encephalopathy), partial or complete blockage (occlusion) of the small arteries and capillaries that supply blood to the retina (branch retinal artery occlusion, or BRAO), and inner ear disease (hearing loss, most notably). MRI of the brain typically reveals “snowball” lesions in the corpus callosum. Three main forms of Susac's syndrome have become apparent. In one form, encephalopathy is the main problem. In the second form, BRAO and hearing loss are the main problems, and there is little or no brain disease. In the third form, encephalopathy is the main problem in the beginning, but recurrent episodes of BRAO become the main problem after the encephalopathy subsides. The encephalopathic form of Susac's syndrome often resolves within 1-3 years. The other forms tend to follow a more prolonged, more chronic, or more recurrent course (for 3-10 years, or more). All forms require immunosuppressive treatment while the disease is active.

Introduction

Although considered rare, Susac syndrome is being recognized more often worldwide and its true frequency in the general population is unknown. This is because the disorder may be misdiagnosed, often as “atypical” multiple sclerosis.

Susac syndrome is an autoimmune disease---specifically, an autoimmune endotheliopathy. "Autoimmune" means that a person’s own immune system is mistakenly attacking its own tissue. An "endotheliopathy" is any disorder that involves injury to the endothelium, which is the thin layer of cells that line the inner walls of blood vessels. In Susac syndrome, the person's own immune system is mistakenly attacking the endothelial lining of the smallest blood vessels (the capillaries, venules and arterioles) in the brain, retina, and inner ear. When the endothelial cells become injured, they tend to swell, and this endothelial cell swelling plays a key role in the partial or complete occlusion (blockage) of the tiny vessels in the brain, retina and inner ear. This blockage results in decreased blood flow through the vessels and, therefore, decreased delivery of oxygen and nutrients to the brain, retina, and inner ear---causing either temporary dysfunction or permanent damage to these three organs, depending on the severity and duration of the decreased blood flow.

Signs & Symptoms

The specific symptoms, severity, and outcome of Susac syndrome vary from one person to another. Commonly, the three main features (encephalopathy, branch retinal arterial occlusions, and hearing loss) are not all present at disease onset, and all three do not necessarily develop in all patients. When patients are first evaluated by a physician, any one of the three main features may be the only feature present, with one or both of the other features appearing only later.

In many patients, headaches (including migraine-like headaches) precede the development of other symptoms of Susac syndrome. A variety of additional neurological findings may develop: cognitive dysfunction (including memory loss, confusion, and decreased executive function), gait disturbance, and slurred speech (dysarthria). Some individuals develop psychiatric symptoms such as paranoia or personality or behavioral changes. The specific neurological symptoms that develop will vary from one person to another.

Branch retinal artery occlusion (BRAO) can cause the patient to notice a “dark spot” or “black area” in their field of vision; or, some patients describe a “curtain or shade being drawn” over a portion of their vision. The medical term for these symptoms is “scotoma.” These symptoms are due to injury to the retina, because of blocked blood flow. The retina is the thin layer of nerve cells that sense light and convert it to nerve signals, which are then relayed to the brain through the optic nerve. Both eyes can be affected in individuals with Susac syndrome. Permanent impairment of vision may occur. BRAOs may occur early in some individuals or later in the course of the disease in others.

Many individuals with Susac syndrome develop hearing loss due to damage to the small, snail-shaped organ of the inner ear known as the cochlea. The cochlea converts sound into nerve impulses to be sent to the brain. The damage to the cochlea is caused by the blockage of blood flow through the small vessels that supply blood to the cochlea. Hearing loss in Susac syndrome is primarily at low frequencies and usually occurs relatively suddenly. It may affect both ears (bilateral). Its severity can range from mild to severe. In severe cases, cochlear implantation is warranted. In some cases, hearing loss may occur before other symptoms of Susac syndrome develop. Hearing loss is often accompanied by intense ringing of the ears (tinnitus). The vestibular apparatus, which is also located in the inner ear, can also be affected by the microvascular endotheliopathy of Susac’s syndrome, resulting in vertigo (dizziness).

The encephalopathic form of Susac syndrome is typically self-limited (i.e., eventually subsides on its own), but may take a long time to resolve and may recur. It usually runs a course of 1-3 years, during which time individuals may experience fluctuating levels of symptoms (relapsing-remitting). Although the encephalopathic form eventually goes away on its own, treatment is necessary to prevent or minimize damage that can occur while the disease is active. Relapse after a long period of remission is rare, but can occur.

Causes

Susac syndrome is an autoimmune endotheliopathy, a disorder in which the body’s immune system mistakenly attacks the inside lining (endothelium) of the walls of the very tiny blood vessels that supply blood to the brain, retina, and inner ear. The exact, underlying reason why this occurs is unknown. Why the microvasculature in the brain, retina, and inner ear are primarily affected is also unclear. The skin may also be involved.

Affected Populations

Susac syndrome primarily affects young women between the ages of 20-40, but has occurred in individuals ranging in age from 9 to 72. Women are affected three times more often than men. Although considered a rare disorder, Susac syndrome is being recognized more often worldwide and may be more common than originally thought. However, because the disorder often goes unrecognized or misdiagnosed, determination of the true frequency of Susac syndrome in the general population has been difficult.

So far, Susac syndrome has not been proven to occur more frequently in any particular ethnic group—but, early data suggest that it may occur more commonly in Caucasian population groups. It has not been known to occur in more than one member of any family, even when the extended family is taken into account.

Susac syndrome was first reported in the medical literature in 1979 by Dr. John Susac. It has also been referred to as “retinopathy, encephalopathy, deafness associated microangiopathy (RED-M)” or “small infarctions of cochlear, retinal and encephalic tissue (SICRET).”

Related Disorders

The encephalopathic form of Susac syndrome is frequently misdiagnosed as multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM). When Susac syndrome presents primarily with hearing loss, tinnitus, and vertigo, it is frequently misdiagnosed as Meniere’s disease.

Multiple sclerosis is a chronic disorder of the central nervous system (CNS) that causes the destruction of the covering (myelin sheath) over the nerves. It is a demyelinating disease. The course of this disease is variable; it may advance, relapse, remit, or stabilize. The demyelinating plaques or patches scattered throughout the central nervous system interfere with the ability of the nerves to communicate (neurotransmission) and can cause a wide range of neurological symptoms including impairment of speech, numbness or tingling sensation in the limbs and difficulty walking. Dysfunction of the bladder and bowel may also be present. (For more information on this disorder, choose “multiple sclerosis” as your search term in the Rare Disease Database.)

Acute disseminated encephalomyelitis (ADEM) is a central nervous system disorder characterized by inflammation of the brain and spinal cord caused by damage to the fatty sheath (myelin) surrounding the nerves. This can occur spontaneously, but usually follows a viral infection or inoculation such as a bacterial or viral vaccine. The symptoms of ADEM usually develop rapidly and may include fever, headaches, vomiting, and fatigue. In severe cases, seizures or coma may develop. Vision loss can also occur due to inflammation of the optic nerve.

Meniere’s disease is a rare disorder that affects the inner ear. Meniere’s disease is characterized by periodic episodes of vertigo or dizziness; fluctuating, progressive, low-frequency hearing loss; ringing in the ears (tinnitus); and a sensation of fullness or pressure in the ear. The disorder usually affects only one ear. As with Susac’s syndrome, hearing loss in Meniere’s disease is caused by damage to the cochlea. The exact cause of Meniere’s disease is unknown. (For more information on this disorder, choose “Meniere” as your search term in the Rare Disease Database.)

Diagnosis

The possibility of Susac syndrome is raised when a patient presents with one or more components of the clinical triad (encephalopathy, BRAO, hearing loss). A diagnosis of definite or probable Susac syndrome is based on presence of at least two components of the triad and documentation of typical “snowball” lesions in the corpus callosum upon brain MRI. The process of making a diagnosis includes, a detailed patient history, a thorough evaluation of all plausible explanations for the illness, and a variety of specialized tests, including magnetic resonance imaging (MRI), fluorescein angiography, and an audiogram.

A complete neurological and ophthalmological examination is essential to making the diagnosis of Susac syndrome. The neurological examination may detect symptoms and/or signs of brain dysfunction. The eye examination should include visual field testing to determine whether BRAOs have affected the patient’s vision. Patients often continue to have 20/20 vision even after BRAOs. Pupils should be dilated and the back of the eye examined carefully. BRAOs should be looked for as well as Gass plaques. Gass plaques appear as small yellow dots in the retinal vessels specifically the arterioles. These Gass plaques are sites of past injury to the endothelium and do not have to be associated at the location of the BRAO.

An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In individuals with Susac syndrome, an MRI typically shows characteristic changes in the brain, especially in the corpus callosum, which is the structure that connects the right and left halves of the brain. The most characteristic MRI abnormality is presence of lesions (“snowballs,” “spokes,” or “holes”) in the central portion of the corpus callosum. These lesions are best seen on sagittal T2 FLAIR images of the corpus callosum.

A fluorescein angiogram (FA) is necessary for individuals suspected of having Susac syndrome, even if they do not have eye symptoms. Fluorescein angiography is an eye test that uses a special dye and a camera to evaluate blood flow (circulation) in the retina. In Susac syndrome FA abnormalities include: evidence of partial or complete branch retinal artery occlusion (BRAO); vessel wall hyperfluorescence (increased intensity of dye staining the walls of vessels); “leakage” of dye; and chronic changes out in the periphery (capillary dropout, neovascularization, microaneurysms), with potential for vitreous hemorrhage.

Individuals with Susac syndrome should also receive a hearing exam (audiogram) to detect any hearing loss. All patients with suspected Susac syndrome should undergo an audiogram, even if they have not noticed any inner ear symptoms.

Adding to the difficulty in making a diagnosis is the fact any one of the components of the clinical triad may be the first and only component present when patients first seek medical attention. This contributes to the probable underreporting of the disorder.

Standard Therapies

Treatment
Although Susac syndrome can sometimes spontaneously subside, early, appropriately aggressive and appropriately sustained treatment is needed, while the disease is active, to avoid or minimize potential irreversible damage to the brain, retina, and inner ear. The two current mainstays of therapy are medications that suppress the activity of the immune system (immunosuppressive agents)—corticosteroid (e.g. prednisone) and intravenous immunoglobulins (IVIG). Additional drugs may also be necessary. Additional drugs that have been used to treat individuals with Susac syndrome include mycophenolate mofetil (Cellcept), azathioprine (Imuran), cyclophosphamide, rituximab, and anti-TNF therapies. Treatment choices depend on the severity of the disease.

For individuals with significant hearing loss, a hearing aid may be indicated. For those with profound hearing loss, cochlear implantatio may be beneficial.

Investigational Therapies

To date, no clinical trials have been developed for the treatment of Susac syndrome. If and when a clinical trial is developed for Susac’s syndrome, information on such a trial will be posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Years Published

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